Background: Thyroid cancer: The incidence of thyroid cancer has doubled over the last two decades. Although most patients with thyroid cancer of follicular cell origin have an excellent prognosis, 10% - 15% will have refractory disease to conventional therapy (resection combined with radioiodine ablation and thyroid hormone for TSH suppression). Chemotherapy and external beam radiation are ineffective in patients with metastatic disease. The overall 10 year survival of patients with metastatic thyroid cancer of follicular cell origin is approximately 40-50%. Adrenocortical carcinoma: Approximately two-thirds of patients who present with adrenocortical carcinoma have locoregional disease and metastasis. Unfortunately, despite combined multimodality therapy, the overall prognosis of patients with adrenocortical carcinoma remains dismal, with a 5-year survival of less than 35%. Summary We are using functional genomics approach to determine the role of candidate genes, differentially expression by mRNA and microRNA expression profiling in thyroid cancer and adrenocortical carcinoma human tumor samples, in in vitro and in vivo models. The role of the candidate genes in regulating the hallmarks of malignant phenotype such as cellular proliferation, invasion and migration, and tumor angiogenesis is being tested using gene knockdown and knockin experiments to identify critical regulators and thus targets for therapy. We are also performing studies to identify novel agents for thyroid cancer and adrenocortical carcinoma. These studies involve using the National Chemical Genomic Center pharmaceutical collection of 2,816 compounds to determine their antiproliferative effect in thyroid cancer and adrenocortical carcinoma cell lines. All of these compounds have either FDA approval for other indications or have investigational new drug designation by the FDA. Thus, translating these findings, after validation of their antiproliferative effect in animal models of thyroid cancer and adrenocortical carcinoma, into clinical trials for patients with advance thyroid cancer and adrenocortical carcinoma would be relatively efficient.